A first generation chemoenzymatic synthesis of (+)-galanthamine

Article abstract of DOI:10.1071/CH10201

A total synthesis of (+)-galanthamine [(+)-1] has been achieved using the readily available and enantiomerically pure metabolite 2 as starting material. The quaternary carbon centre (C8a) associated with target 1 was constructed using the EschenmoserClais

Full text of DOI:10.1071/CH10201

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 1437–1447
A First Generation Chemoenzymatic Synthesis
of (+)-Galanthamine
Martin G. Banwell,A,B Xinghua Ma,A Ochitha P. Karunaratne,A
and Anthony C. WillisA
AResearch School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra, ACT 0200, Australia.
BCorresponding author. Email: mgb@rsc.anu.edu.au
A total synthesis of (+)-galanthamine [(+)-1] has been achieved using the readily available and enantiomerically pure
metabolite 2 as starting material. The quaternary carbon centre (C8a) associated with target 1 was constructed using the
Eschenmoser–Claisen rearrangement reaction.
Manuscript received: 17 May 2010.
Manuscript accepted: 6 July 2010.
HO
O
HO
O
Introduction
7
A
8
The alkaloid (–)-galanthamine [(–)-1, Fig. 1] has been obtained
from various Amaryllidaceae species including daffodils, the
Red Spider Lily (Lycoris radiata), and the Caucasian snow-
drop (Galanthus woronowii).[1,2] Its effectiveness as a centrally
acting, selective, reversible, and competitive inhibitor of acetyl-
cholinesterase has resulted in galanthamine being introduced
into the clinic in both the USA and Europe for the symp-
tomatic treatment of mild to moderate forms of Alzheimer’s
disease.[1,2] While the compound produces beneficial effects
even after treatment is terminated there are no indications that
it can arrest the course of the process of dementia.[2] The 2.3 Å
resolution X-ray crystal structure of acetylcholinesterase com-
plexed with (–)-1 was reported in 1991[3] and in the intervening
period this has provided a rational basis for the development
of superior analogues.[2] These continue to be sought.[4] Inter-
estingly, a recent report[5] suggests that (–)-1 could serve as an
antidote to poisoning by the nerve agent sarin and other toxic
organophosphorous compounds.
The intriguing structure and biological properties of (–)-
1 have prompted extensive synthetic studies, the majority of
which have provided the alkaloid in racemic form.[2] Barton
and Kirby carried out the initial and most significant early stud-
ies. They employed a biomimetic and intramolecular phenolic
coupling reaction to simultaneously establish the quaternary car-
bon centre and the tetracyclic framework of galanthamine.[6]
Various refinements of this basic approach have since been intro-
duced including ones that lead to enantiomerically enriched (–)-
1.[6b,7] A particularly notable variant has recently been reported
by Magnus and coworkers.[8] Several syntheses of (−)- or
(+)-1 have been achieved using chiral pool-derived starting
materials[2,9] but Trost and Toste were the first to devise a cat-
alytic asymmetric synthesis of the natural product.[10] A notable
additional feature of their work was the use of an intramolecular
Heck reaction to establish the quaternary carbon centre (C8a)
of target (−)-1. Others have also followed this approach.[11] In
2006,Tu and coworkers described[12] the use of a semi-pinacolic
8a
OH
OH
N
N
B
D
C
Br
MeO
MeO
(Ϫ)-1
(ϩ)-1
2
Fig. 1. Structures of (−)-galanthamine [(−)-1], (+)-galanthamine [(+)-1],
and (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol (2).
rearrangementtoconstructthequaternarycarboncentreof( )-1
while Cho et al. have used an intramolecular Diels–Alder
reaction for the same purpose.[13]
Herein we report a total synthesis of (+)-1 from the enan-
tiomerically pure cis-1,2-dihydrocatechol 2. Compound 2 is
readily obtained through the whole-cell biotransformation of
bromobenzene using a genetically engineered microorganism
that over-expresses the responsible enzyme, namely toluene
dioxygenase.[14] The synthesis exploits an Eschenmoser–
Claisen rearrangement[15] to establish the quaternary carbon
of the target, a bromonium ion-mediated cyclization to form
the benzofuran subunit,[16] and a Pictet–Spengler reaction[17] to
complete the formation of the seven-membered and nitrogen-
containing D-ring.
Results and Discussion
The synthesis of the substrate required for the Eschenmoser–
Claisen rearrangement is outlined in Scheme 1 and starts with
the conversion of the dihydrocatechol 2 into the corresponding
and well known acetonide 3[14a] that is, without purification,
immediately subjected to epoxidation with m-chloroperbenzoic
acid (m-CPBA) to give the previously reported oxirane 4[14a]
(90% over two steps). Regioselective nucleophilic ring-opening
of compound 4 with acetic acid and using phosphoric acid as
catalyst[18] afforded the hydroxy-ester 5 (81%) that was treated
© CSIRO 2010
10.1071/CH10201
0004-9425/10/101437

1438
M. G. Banwell et al.
(MeO)2CMe2,
acetone,
p -TsOH·H2O
OMOM
O
OMOM
O
O
HO
OH
OH
O
O
O
O
m-CPBA
MeC(OMe)2NMe2,
toluene
O
8a
O
i-PrO
i-PrO
Br
Br
Br
CONMe2
MeO
2
3
4
MeO
HO
10
11
OH
OH
AcOH,
H3PO4
Br2,
toluene
Br
CONMe2
Br2,
toluene,
acetone
O
B(OH)2
OMOM
O
H2,
OR
Br
K2CO3,
MeOH
10% Pd on C,
K2CO3
i-PrO
HO
AcO
O
O
ϩ
MeO
Br
O
MeO
12
Br
7
HO
X
HO
O
MOM-Cl,
DMAP,
DIPEA
8
5 R ϭ H
O
OH
6 R ϭ MOM
O
CONMe2
CONMe2
Pd[0],
Na2CO3
O
O
MeO
X
MeO
OMOM
O
OMOM
O
13
14 X ϭ Br
15 X ϭ H
H2, 10% Pd on C,
K2CO3
HO
HO
(i) ClCH2CO2H,
DIAD, Ph3P,
toluene
O
O
Scheme 2.
i-PrO
i-PrO
(ii) K2CO3,
MeOH
MeO
MeO
a transannular nucleophilic displacement reaction involving one
of the hydroxy groups unmasked in the preceding step. To cir-
cumvent such difficulties, the bromination step was carried out
in toluene and the reaction mixture then treated with acetone. In
this manner the dibromoacetonide 14 was now obtained in 93%
yield and when this was subjected to hydrogenolysis under the
previously described conditions then the required benzofuran
derivative 15 was obtained in 68% yield.
9
10
Scheme 1.
with methoxymethyl chloride (MOM-Cl) in the presence of 4-
(N,N-dimethylamino)pyridine (DMAP)/diisopropylethylamine
(DIPEA) to give the ester-ether 6 in 91% yield. Cleavage of the
acetate residue within compound 6 was effected with potassium
carbonate in methanol and the resulting alcohol 7 (95%) sub-
jected to Suzuki–Miyaura cross-coupling[19] with the boronic
acid 8[20] to give the arylated cyclohexene 9 in 98% yield.
Reaction of compound 9 under Mitsunobu conditions[21] using
chloroacetic acid as the nucleophile followed by treatment of the
crudeproductwithpotassiumcarbonateinmethanolaffordedthe
epimeric alcohol 10 in 93% yield.
The acquisition of compound 10 allowed for an investiga-
tion of the pivotal Ecshenmoser–Claisen rearrangement as well
as the construction of the benzofuran moiety associated with
the galanthamine. In the event (Scheme 2), treatment of allylic
alcohol 10 with the dimethylacetal of N,N-dimethylacetamide
in refluxing toluene for 7 days resulted in the smooth conver-
sion of the substrate into the acetamide 11 (89%). Compound 11
was immediately subjected to reaction with molecular bromine
under conditions originally defined by Mulzer et al.[16] and used
by Chida and coworkers[19] in their recently reported synthesis
of (+)-1.When this reaction was run in toluene then the dibromi-
nated triol 12 was obtained in 69% yield and its structure was
confirmed by single-crystal X-ray analysis.[22] Clearly, the HBr
generated in this reaction serves to catalyze acetonide group
hydrolysis by adventitious water. In an effort to hydrogenolyt-
ically remove the bromines in product 12 it was treated with a
combination of dihydrogen, 10% Pd on C, and potassium car-
bonate. However, rather than obtaining the desired outcome, the
7-oxanorbornene 13 (67%) was the only isolable product of the
reaction. Its structure was also confirmed by X-ray crystallo-
graphic methods.[22] This unanticipated product must arise from
The introduction of the ꢀ7-double bond into the A-ring of
the developing galanthamine framework was readily achieved
using the Corey–Winter olefination reaction[23] (Scheme 3). As
a prelude to carrying out such a reaction, the free hydroxy group
within compound 15 was protected as the corresponding acetate
16 (90%) using standard conditions and the latter compound
then subjected to acetonide hydrolysis using acetic acid in water.
The diol (94%) so-formed was immediately treated with thio-
phosgene and the cyclic thiocarbonate 17 thereby obtained in
99% yield. Reaction of compound 17 with trimethylphosphite
resulted in the desired conversion and thus produced allylic
acetate 18 in 72% yield.
The completion of the synthesis of (+)-1 from precursor 18
requires construction of the seven-membered D-ring. This was
ultimately carried out using a Pictet–Spengler reaction as shown
in Scheme 4. Prior to manipulation of the amide unit within
compound 18, the acetate moiety was removed with potassium
carbonate in methanol and the resulting alcohol 19 (95%) repro-
tected as the corresponding tert-butyldiphenylsilyl (TBDPS)
ether[24] 20 (95%) under standard conditions. The structure of
compound 19 was also confirmed by single-crystal X-ray anal-
ysis. The derived ORTEP diagram is shown in Fig. 2. Reaction
of amide 20 with Superhydride (lithium triethylborohydride)[25]
resulted in reduction of the amide residue and produc-
tion of the primary alcohol 21 (95%) that was oxidized to
the corresponding aldehyde in 98% yield using the Dess–
Martin periodinane (DMP).[26] Reaction of this aldehyde with
N-bromosuccinimide (NBS) in the presence of catalytic amounts
of α,αꢀ-azobisisobutyronitrile (AIBN) followed by methylamine

Chemoenzymatic Synthesis of (+)-Galanthamine
1439
RO
AcO
O19
C4
O
O
S
(i) AcOH,
water
O
O
CONMe2
CONMe2
(ii) Cl2CS,
DMAP
O
O
C5
C6
C3
C2
MeO
Ac2O,
DMAP,
pyridine
MeO
O21
15 R ϭ H
16 R ϭ Ac
17
O1
AcO
C22
(MeO)3P,
toluene
C17
C7
C18
C13
C14
CONMe2
O
C16
C8
C15
MeO
18
C9
O20
Scheme 3.
C11
N10
C12
TBDPSO
RO
Superhydride™
OH
CONMe2
O
O
Fig. 2. View of compound 19 (CCDC 739080) with labelling of selected
atoms. Anisotropic displacement ellipsoids display 30% probability levels.
Hydrogen atoms are drawn as circles with small radii.
MeO
MeO
18 R ϭ Ac
21
K2CO3,
MeOH
19 R ϭ H
TBDPS-Cl,
20 R ϭ TBDPS
imidazole
of 9 into 10 afforded the ester 25 (93%) that upon reaction with
lithium aluminum hydride (LAH) gave (+)-1 in 85% yield and
as a white crystalline solid, mp 121–124◦C (lit.[9b] mp 124–
125◦C), [α]D +108.8 (c 0.4, chloroform) {lit.[9b] [α]D +115.5
(c 0.5, ethanol)}. The 1H NMR, 13C NMR, and IR spectro-
scopic and mass spectrometry data derived from this material
were in full accord with the assigned structure and matched
those reported[9b] for ( )-, (−)-, and (+)-1 as well as those
derived from an authentic sample of the natural product (see
(i) DMP (ii) NBS, AIBN (cat.),
CCl4 then MeNH2
RO
HO
O
(H2CO)n,
TFA
O
N
CONHMe
O
1
MeO
MeO
Fig. 3 for a comparison of the 800 MHz H NMR spectra of
the two samples).
24
22 R ϭ TBDPS
23 R ϭ H
TBAF,
THF
The first generation synthesis of (+)-1 described here should
be capable of considerable refinement, especially in regards to
the use of protecting groups and the sequence of reactions used
to construct the D-ring from the product of the Eschenmoser–
Claisen rearrangement. Furthermore, since the enantiomer of
compound 2 is also available,[27] the present work represents a
formal total synthesis of the natural product itself, that is (−)-1.
In this context it is worth noting that the allylic alcohol 9 reacts
with the dimethylacetal of N,N-dimethylacetamide in reflux-
ing toluene and thereby affords (in 37% yield) the C8a-epimer
(galanthamine numbering) of compound 11 and thus possesses
thesameconfigurationatthisquaternarycarbonasseenin(−)-1.
In principle, then, the chemistry described herein could be used
to make both the natural and the non-natural enantiomeric forms
of galanthamine from the same enantiomeric form of the starting
material 2. Work aimed at developing such possibilities is now
underway in these laboratories.
ClCH2CO2H,
DIAD, Ph3P, toluene
O
HO
O
O
Cl
LAH
O
N
D
N
O
MeO
MeO
25
(ϩ)-1
Scheme 4.
(to intercept the intermediate acyl halide)[12] resulted in the for-
mation of the amide 22 (80%). Treatment of compound 22 with
tetra-n-butylammonium fluoride (TBAF) resulted in removal of
the TBDPS group and the rather insoluble alcohol 23 (85%) so-
formed was then treated with a mixture of paraformaldehyde
and trifluoroacetic acid (TFA) so as to effect the pivotal Pictet–
Spengler reaction and thereby generate the hydroxy-lactam 24,
which was obtained in 88% yield as a white crystalline solid,
mp 232–235◦C. Subjection of compound 24 to a Mitsunobu
reaction under the same conditions as used for the conversion
Experimental
General Experimental Procedures
Proton (1H) and carbon (13C) NMR spectra were recorded on
a Varian Mercury machine operating at 300 MHz. 800 MHz
1H NMR spectra were recorded on a Bruker AV800 machine.
Unless otherwise specified, spectra were acquired at 20◦C
in deuterochloroform (CDCl3) that had been filtered through

1440
M. G. Banwell et al.
HO
O
N
MeO
(ϩ)-1
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
ppm
HO
O
N
MeO
(Ϫ)-1
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
ppm
Fig. 3. The 800 MHz 1H NMR spectra of synthetically derived (+)-galanthamine (top) and naturally derived (−)-galanthamine (bottom) (both spectra
recorded in CDCl3).
basic alumina immediately before use. Chemical shifts are
recorded as δ values in parts per million [ppm]. Infrared
spectra (νmax) were normally recorded on a Perkin–Elmer
1800 Series FTIR Spectrometer and samples were analyzed
as thin films on KBr plates (for liquids) or as a KBr disc
(for solids). Low-resolution electrospray ionization (ESI) mass
spectra were recorded on a Micromass–Waters LC-ZMD sin-
gle quadrupole liquid chromatograph-mass spectrometer while
low- and high-resolution electron impact (EI) mass spectra
were recorded on a VG Fisons AUTOSPEC three-sector double-
focusing instrument. Melting points were measured on Reichert
hot-stage microscope or a Stanford Research Systems Optimelt–
Automated Melting Point System and were uncorrected. Ana-
lytical TLC was performed on aluminium-backed 0.2 mm thick
silica gel 60 F254 plates as supplied by Merck. Eluted plates
were visualized using a 254 nm UV lamp and/or by treatment
with a suitable dip followed by heating. These dips included
a mixture of phosphomolybdic acid/ceric sulfate/sulfuric acid
(conc.)/water (37.5 g/7.5 g/37.5 g/720 mL). The retardation fac-
tor (RF) values cited here have been rounded at the first decimal
point. Flash chromatographic separations were carried out fol-
lowing protocols defined by Still et al.[28] with silica gel 60
(0.040–0.0063 mm) as the stationary phase and using theAR- or
HPLC-grade solvents indicated. Starting materials and reagents
were generally available from the Sigma–Aldrich, Merck, TCI,
Strem, or Lancaster Chemical Companies and were used as
supplied. Drying agents and other inorganic salts were pur-
chased from the AJAX, BDH, or Unilab Chemical Companies.
Tetrahydrofuran (THF), dichloromethane, and benzene were
dried using a Glass Contour solvent purification system that
is based upon a technology originally described by Grubbs
et al.[29] Spectroscopic grade solvents were used for all analy-
ses. Where necessary, reactions were performed under a nitrogen
atmosphere.
Specific Synthetic Procedures and Product
Characterization
Compound 5
A magnetically stirred solution of epoxide 4[30] (5.6 g,
22.7 mmol) in acetic acid (30 mL) was treated with phospho-
ric acid (0.1 mL). After stirring at 18◦C for 1 h the reaction
mixture was quenched with NH4Cl (150 mL of a saturated
aqueous solution) and ethyl acetate (50 mL).The separated aque-
ous phase was extracted with ethyl acetate (4 × 50 mL) and
the combined organic phases were then dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The residue
thus obtained was subjected to flash chromatography (silica,
1.5:1 v/v ethyl acetate/hexane elution) to provide, after concen-
tration of the appropriate fractions (RF 0.4 in 8:2.5:5.5 v/v/v
ethyl acetate/dichloromethane/hexane), acetate 5 (5.7 g, 81%)
as a white, crystalline solid, mp 107–108◦C, [α]D +68.5 (c 0.8,
CHCl3) [Found: M+•, 306.0104. C11H1579BrO5 requires M+•
,
306.0103]. δH (300 MHz) 6.05 (d, J 2.3, 1H), 5.13 (m, J 8.0,
1H), 4.64 (d, J 6.3, 1H), 4.17 (dd, J 8.2 and 6.3, 1H), 3.76 (td,
J 10.7 and 2.6, 1H), 3.33 (br s, 1H), 2.06 (s, 3H), 1.48 (s, 3H),

Chemoenzymatic Synthesis of (+)-Galanthamine
1441
1.36 (s, 3H). δC (75 MHz) 170.6 (C), 131.2 (CH), 120.7 (C),
111.1 (C), 77.4 (CH), 76.9 (CH), 72.6 (CH), 70.6 (CH), 28.0
(CH3), 26.0 (CH3), 21.0 (CH3). νmax (KBr)/cm−1 3467, 2989,
2936, 1748, 1649, 1373, 1234, 1081, 1050, 1021, 978, 869. m/z
(EI, 70 eV) 308 and 306 (M+•, both 11%), 293 and 291 (96 and
100), 248 and 246 (both 35), 191 and 189 (75 and 76), 110 (76),
109 (73), 101 (85), 81 (65), 59 (78).
(41 and 43), 191 and 189 (25 and 34), 161 (25), 145 (100),
110 (42), 109 (40), 58 (75).
Compound 8
Step i: A magnetically stirred solution of tert-butylamine
(6 mL, 56.8 mmol) in toluene (100 mL) was cooled to between
−50 and −40◦C then treated with molecular bromine (1.4 mL,
27.3 mmol). The resulting mixture was stirred at this tempera-
ture for 1 h and then treated with guaiacol (3.00 g, 24.2 mmol)
and allowed to warm to −10◦C over ∼4 h. The ensuing mixture
was quenched with Na2S2O3 (100 mL of a 10% w/v aqueous
solution) and then stirred for a further 1 h while being allowed
to warm to room temperature. The separated aqueous phase
was extracted with ethyl acetate (4 × 50 mL) and the combined
organic phases were washed with NH4Cl (1 × 100 mL of a sat-
urated aqueous solution) before being dried (MgSO4), filtered,
and concentrated under reduced pressure. The light-yellow oil
thusobtainedwasdissolvedinN,N-dimethylformamide(50 mL)
and the resulting solution treated with 2-bromopropane (4.5 mL,
47.9 mmol) and potassium carbonate (8.0 g, 57.9 mmol). After
stirring the ensuing mixture at 18◦C for 18 h it was treated
with water (100 mL) and diethyl ether (100 mL). The separated
aqueous phase was extracted with diethyl ether (2 × 50 mL) and
the combined organic phases were then washed with NH4Cl
(2 × 100 mL of a saturated aqueous solution) before being dried
(MgSO4), filtered, and concentrated under reduced pressure.
Subjection of the ensuing residue to flash chromatography
(silica, 1:20 v/v ethyl acetate/hexane elution) and concentra-
tion of the appropriate fractions (RF 0.5 in 0.5:2.5:5.5 v/v/v
ethyl acetate/dichloromethane/hexane) afforded the bromide
precursor[31] to compound 8 (5.5 g, 93% over two steps) as a
clear, light-yellow syrup [Found: M+•, 244.0116. C10H1379BrO2
requires M+•, 244.0099]. δH (300 MHz) 7.09 (dd, J 7.7 and 1.2,
1H), 6.87–6.77 (complex m, 2H), 4.54 (sept, J 6.2, 1H), 3.77 (s,
3H), 1.31 (d, J 6.2, 6H). δC (75 MHz) 154.0 (C), 144.6 (C), 124.8
(CH), 124.3(CH), 118.6(C), 111.5(CH), 75.7(CH), 55.8(CH3),
22.4(2 × CH3). νmax (KBr)/cm−1 2977, 2936, 2837, 1582, 1572,
1474, 1451, 1435, 1261, 1233, 1105, 1037, 931, 833, 761. m/z
(EI, 70 eV) 246 and 244 (M+•, 2 and 3%), 204 and 202 (37 and
38), 167 (24), 149 (77), 83 (31), 57 (86), 43 (100).
Compound 6
Chloromethyl methyl ether (42 mL, technical grade) was
added to a magnetically stirred solution of compound 5 (6.9 g,
22.5 mmol), DMAP (13.7 g, 112.1 mmol), and DIPEA (117 mL,
672.2 mmol) in dichloromethane (80 mL) maintained under
a nitrogen atmosphere. After stirring at 18◦C for 18 h the
reaction mixture was treated with NH4Cl (100 mL of a sat-
urated aqueous solution) and the separated aqueous phase
was extracted with dichloromethane (1 × 50 mL). The com-
bined organic layers were washed with NH4Cl (1 × 150 mL
of a saturated aqueous solution) and NaHCO3 (1 × 150 mL
of a saturated aqueous solution) before being dried (MgSO4),
filtered, and concentrated under reduced pressure. The ensu-
ing residue was subjected to flash chromatography (silica, 1:4
v/v ethyl acetate/hexane elution) to afford, after concentration
of the appropriate fractions (RF 0.4 in 2:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane), MOM-ether 6 (7.2 g, 91%)
as a white, crystalline solid, mp 64.5–66.0◦C, [α]D +83.0 (c
0.9, CHCl3) [Found: M+•, 350.0369. C13H1979BrO6 requires
M
+•, 350.0365]. δH (300 MHz) 6.10 (d, J 2.8, 1H), 5.21 (dddd,
J 7.3, 2.7, 1.8, and 1.0, 1H), 4.82 (d, J 6.6, 1H), 4.72 (d, J 6.6, 1H),
4.65 (dd, J 6.0 and 0.7, 1H), 4.27 (dd, J 7.3 and 6.0, 1H), 3.90 (t,
J 7.5, 1H), 3.37 (s, 3H), 2.07 (s, 3H), 1.52 (s, 3H), 1.39 (s, 3H).
δC (75 MHz) 170.3 (C), 130.8 (CH), 121.9 (C), 111.0 (C), 96.6
(CH2), 77.0 (2 × CH), 74.0 (CH), 71.6 (CH), 55.8 (CH3), 27.8
(CH3), 26.3 (CH3), 21.0 (CH3). νmax (KBr)/cm−1 2988, 2936,
2825, 1749, 1651, 1454, 1440, 1374, 1232, 1084, 1047, 921,
869, 794. m/z (EI, 70 eV) 352 and 350 (M+•, both 10%), 337
and 335 (both 31), 290 and 288 (17 and 16), 203 (24), 189 (32),
145 (100), 59 (36).
Compound 7
Potassium carbonate (4.3 g, 31.1 mmol) was added to a mag-
netically stirred solution of MOM-ether 6 (7.2 g, 20.5 mmol) in
methanol (40 mL) and after being maintained at 18◦C for 1 h
the reaction mixture was concentrated under reduced pressure.
The solid mass thus obtained was treated with NH4Cl (100 mL
of a saturated aqueous solution) and ethyl acetate (100 mL) and
the separated aqueous phase was extracted with ethyl acetate
(2 × 50 mL). The combined organic phases were then dried
(MgSO4), filtered, and concentrated under reduced pressure
and the ensuing residue subjected to flash chromatography
(silica, 1:8:16 v/v/v methanol/ethyl acetate/hexane elution) to
give, after concentration of the appropriate fractions (RF 0.3 in
4:2.5:5.5 v/v/v ethyl acetate/dichloromethane/hexane), alcohol
7 (6.0 g, 95%) as a clear, light-yellow oil, [α]D +45.8 (c 0.6,
Step ii: n-Butyllithium (11.4 mL of a 2.5 M solution in hex-
anes, 28.5 mmol) was added, dropwise, to a magnetically stirred
solution of the above-mentioned bromide (4.35 g, 17.76 mmol)
and triisopropyl borate (6.1 mL, 26.4 mmol) in dryTHF (60 mL)
maintained at −78◦C under a nitrogen atmosphere. Stirring
was continued for 3 h and then the reaction mixture was
warmed to 0◦C and treated with NH4Cl (100 mL of a sat-
urated aqueous solution). The separated aqueous phase was
extracted with diethyl ether (3 × 30 mL) and the combined
organic phases were then washed with brine (1 × 200 mL of a
saturated aqueous solution) before being dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The ensuing
light-yellow oil was subjected to flash chromatography (silica,
1:5 v/v ethyl acetate/hexane elution) to give, after concentra-
tion of the appropriate fractions (RF 0.4 in 2:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane), boronic acid 8[31] (3.06 g,
82%) as a white, crystalline solid, mp 77–79◦C [Found:
CHCl3) [Found: M+•, 308.0264. C11H1779BrO5 requires M+•
,
308.0259]. δH (300 MHz) 6.27 (d, J 3.3, 1H), 4.78 (dd, J 16.6 and
6.9, 2H), 4.66 (d, J 5.9, 1H), 4.31 (t, J 6.5, 1H), 4.08 (br s, 1H),
3.78 (br s, 1H), 3.72 (t, J 6.5, 1H), 3.43 (s, 3H), 1.53 (s, 3H),
1.41 (s, 3H). δC (75 MHz) 133.3 (CH), 121.2 (C), 111.1 (C),
97.8 (CH2), 80.2 (CH), 77.0 (CH), 76.6 (CH), 69.6 (CH), 56.1
(CH3), 28.1 (CH3), 26.2 (CH3). νmax (KBr)/cm−1 3420, 2987,
2933, 1645, 1382, 1218, 1153, 1107, 1067, 1036, 988, 915, 868.
m/z (EI, 70 eV) 310 and 308 (M+•, 55 and 54%), 295 and 293
M
+•, 210.1064. C10H1511BO4 requires M+•, 210.1063]. δH
(300 MHz) 7.42 (dd, J 7.3 and 1.3, 1H), 7.10 (t, J 8.1, 1H),
7.02 (dd, J 8.1 and 1.3, 1H), 6.89 (s, 2H), 4.77 (sept, J 6.2, 1H),
3.85 (s, 3H), 1.31 (d, J 6.2, 6H). δC (75 MHz) 151.8 (3 × C),
127.4 (CH), 124.2 (CH), 115.8 (CH), 75.4 (CH), 55.9 (CH3),
22.5 (2 × CH3). νmax (KBr)/cm−1 3365, 2983, 2838, 1594,

1442
M. G. Banwell et al.
1575, 1473, 1343, 1264, 1085, 1031, 773, 739, 692. m/z (EI,
70 eV) 210 (M+•, 4%), 196 (94), 195 (47), 178 (53), 150 (100),
149 (56), 135 (37), 107 (36), 77 (22), 59 (6), 53 (16).
J 8.2 and 6.6, 2H), 4.55 (t, J 5.6, 1H), 4.49 (t, J 3.4, 1H), 4.40
(sept, J 6.1, 1H), 4.08 (dd, J 5.6 and 3.7, 1H), 3.83 (s, 3H), 3.45
(s, 3H), 2.40 (br s, 1H), 1.38 (s, 3H), 1.32 (s, 3H), 1.25 (d, J
6.1, 3H), 1.16 (d, J 6.1, 3H). δC (75 MHz) 153.3 (C), 144.6 (C),
138.2 (C), 135.0 (C), 130.4 (CH), 123.8 (CH), 122.6 (CH), 112.0
(CH), 109.4 (C), 97.6 (CH2), 78.8 (CH), 75.3 (CH), 74.9 (CH),
73.9 (CH), 65.9 (CH), 56.1 (CH3), 55.9 (CH3), 27.8 (CH3), 26.2
(CH3), 22.6 (CH3), 22.5 (CH3). νmax (KBr)/cm−1 3452, 2927,
2854, 1576, 1459, 1371, 1260, 1219, 1112, 1069, 1035, 918,
735. m/z (EI, 70 eV) 394 (M+•, 63%), 336 (10), 320 (8), 244
(21), 232 (81), 215 (57), 204 (60), 203 (100), 190 (85), 161 (48),
145 (54), 115 (28).
Compound 9
Pd(Ph3P)4 (836 mg) was added to a magnetically stirred mix-
ture of alcohol 7 (4.47 g, 14.46 mmol), boronic acid 8 (3.46 g,
16.47 mmol), Na2CO3 (20 mL of a 2.0 M aqueous solution), and
benzene (80 mL) maintained under a nitrogen atmosphere. The
ensuing mixture was heated at reflux for 18 h and then cooled
to 18◦C and treated with NH4Cl (100 mL of a saturated aque-
ous solution). The separated aqueous phase was extracted with
ethyl acetate (2 × 40 mL) and the combined organic phases were
then dried (MgSO4), filtered, and concentrated under reduced
pressure. Subjection of the ensuing residue to flash chromato-
graphy (silica, 1:2 v/v ethyl acetate/hexane elution) gave, after
concentration of the appropriate fractions (RF 0.3 in 4:2.5:5.5
v/v/v ethyl acetate/dichloromethane/hexane), alcohol 9 (5.62 g,
98%) as a clear, light-yellow oil, [α]D −19.7 (c 0.9, CHCl3)
[Found: M+•, 394.1994. C21H30O7 requires M+•, 394.1992].
δH (300 MHz) 7.03 (t, J 7.8, 1H), 6.91–6.85 (complex m, 2H),
5.94 (d, J 2.3, 1H), 5.30 (d, J 6.3, 1H), 4.87 (dd, J 15.1 and
6.9, 2H), 4.36 (sept, J 6.2, 1H), 4.29 (dd, J 8.2 and 6.2, 1H),
4.20 (m, 1H), 4.07 (d, J 3.4, 1H), 3.83 (s, 3H), 3.63 (t, J 7.9,
1H), 3.48 (d, J 0.5, 3H), 1.45 (s, 3H), 1.33 (s, 3H), 1.26 (d, J
6.2, 3H), 1.15 (d, J 6.2, 3H). δC (75 MHz) 153.1 (C), 144.6 (C),
134.8 (C), 134.2 (C), 131.8 (CH), 123.8 (CH), 122.3 (CH), 111.9
(CH), 110.2 (C), 98.1 (CH2), 83.3 (CH), 76.5 (CH), 75.5 (CH),
74.4 (CH), 69.4 (CH), 55.9 (CH3), 55.8 (CH3), 28.3 (CH3), 26.1
(CH3), 22.7 (CH3), 22.6 (CH3). νmax (KBr)/cm−1 3438, 2979,
2933, 1576, 1460, 1380, 1371, 1259, 1219, 1108, 1059, 867, 785.
m/z (EI, 70 eV) 394 (M+•, 56%), 336 (14), 294 (13), 244 (31),
232 (71), 231 (65), 215 (64), 214 (60), 204 (61), 203 (100),
190 (81), 161 (46), 145 (33).
Compound 11
A magnetically stirred solution of compound 10 (3.18 g,
8.06 mmol) in toluene (50 mL) was treated with N,N-
dimethylacetamide dimethyl acetal (13 mL, 80.0 mmol) and the
ensuing mixture heated (oil bath) at reflux. When TLC analysis
indicated that no starting material remained (∼7 days), the reac-
tion mixture was cooled and then concentrated under reduced
pressure. Subjection of the ensuing residue to flash chromato-
graphy (silica, 1:10:40 v/v/v methanol/hexane/ethyl acetate elu-
tion) and concentration of the appropriate fractions (RF 0.3 in
8:2.5:5.5 v/v/v ethyl acetate/dichloromethane/hexane) afforded
amide 11 (3.33 g, 89%) as a clear, colourless oil, [α]D +58.0 (c
1.0, CHCl3) [Found: M+•, 463.2569. C25H37NO7 requires M+•
,
463.2570]. δH (300 MHz) 6.97–6.86 (complex m, 2H), 6.77 (dd,
J 7.9 and 1.6, 1H), 6.53 (d, J 10.5, 1H), 5.82 (dd, J 10.5 and 3.9,
1H), 5.08 (sept, J 6.2, 1H), 4.92 (dd, J 5.4 and 1.2, 1H), 4.77
(dd, J 18.4 and 6.7, 2H), 4.47 (dd, J 5.4 and 3.7, 1H), 4.17 (m,
1H), 3.77 (s, 3H), 3.58 (d, J 15.6, 1H), 3.39 (s, 3H), 3.11 (d,
J 15.6, 1H), 2.88 (s, 3H), 2.76 (s, 3H), 1.27 (s, 6H), 1.26 (d, J
6.2, 3H), 1.23 (d, J 6.2, 3H). δC (75 MHz) 170.2 (C), 151.9 (C),
144.4 (C), 137.2 (CH), 135.4 (C), 123.7 (CH), 122.9 (CH), 121.4
(CH), 111.2 (CH), 107.8 (C), 95.5 (CH2), 79.5 (CH), 78.2 (CH),
73.7 (CH), 72.9 (CH), 55.7 (CH3), 55.4 (CH3), 45.8 (C), 43.0
(CH2), 37.6 (NCH3), 35.3 (NCH3), 27.6 (CH3), 26.0 (CH3),
22.7 (CH3), 22.4 (CH3). νmax (KBr)/cm−1 2983, 2938, 2836,
1657, 1580, 1455, 1380, 1263, 1214, 1150, 1106, 1039, 918, 737.
m/z (EI, 70 eV) 463 (M+•, 41%), 402 (62), 376 (84), 302 (38),
244 (53), 229 (52), 215 (57), 162 (63), 87 (96), 72 (96), 46 (78),
45 (100), 43 (85).
Compound 10
A solution of compound 9 (5.62 g, 14.25 mmol) in toluene
(150 mL) maintained at 18◦C was treated with α-chloroacetic
acid(5.4 g, 57.1 mmol), triphenylphosphine(16.8 g, 64.0 mmol),
and diisopropyl azodicarboxylate (9.8 mL, 49.8 mmol). After
18 h the reaction mixture was treated with NaHCO3 (100 mL of a
saturated aqueous solution) and the separated aqueous phase was
extracted with ethyl acetate (2 × 25 mL). The combined organic
phases were then washed with NH4Cl (100 mL of a saturated
aqueous solution) before being dried (MgSO4), filtered, and con-
centrated under reduced pressure. The ensuing viscous mixture
was dissolved in methanol (50 mL) and the resulting solution
treated with anhydrous potassium carbonate (2.2 g, 15.9 mmol).
After stirring at 18◦C for 1 h, the reaction mixture was con-
centrated under reduced pressure and the residue thus obtained
was treated with water (50 mL), NH4Cl (150 mL of a saturated
aqueous solution), and ethyl acetate (100 mL). The separated
aqueous phase was extracted with ethyl acetate (3 × 40 mL) and
the combined organic phases were then dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The resulting
light-yellow oil was subjected to flash chromatography (silica,
1:1 v/v ethyl acetate/hexane elution) to give, after concentra-
tion of the appropriate fractions (RF 0.3 in 4:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane), alcohol 10 (5.22 g, 93% over
two steps from 9) as a clear, light-yellow oil, [α]D −68.0 (c
Compound 12
Molecular bromine (0.6 mL, 11.71 mmol) was added to
a magnetically stirred solution of compound 11 (1.83 g,
3.95 mmol) in toluene (60 mL) maintained at 18◦C. After 18 h
the reaction mixture was concentrated under reduced pressure
and the residue thus obtained subjected to flash chromatography
(silica, 1:3:6 v/v/v methanol/hexane/ethyl acetate elution).
Concentration of the appropriate fractions (RF 0.5 in 1:3 v/v
methanol/ethyl acetate) then gave dibromotriol 12 (1.35 g, 69%)
as a white, crystalline solid, mp 192–196◦C, [α]D +114.0 (c
0.5, CH3OH) [Found: (M + Na)+, 515.9640. C17H2179Br2NO6
requires (M + Na)+, 515.9633]. δH (300 MHz) 7.42 (d, J 2.0,
1H), 6.95 (d, J 2.0, 1H), 5.10 (d, J 9.0, 1H), 4.46 (d, J 3.4, 1H),
4.36 (dd, J 9.0 and 2.6, 1H), 4.01 (dd, J 4.4 and 3.4, 1H), 3.97
(dd, J 4.4 and 2.6, 1H), 3.84 (s, 3H), 3.05 (d, J 14.6, 1H), 2.85 (s,
3H), 2.77 (s, 3H), 2.56 (d, J 14.6, 1H). δC (75 MHz) 172.8 (C),
147.3 (C), 147.0 (C), 136.8 (C), 123.5 (CH), 117.3 (CH), 113.9
(C), 91.2 (CH), 75.0 (CH), 74.7 (CH), 71.8 (CH), 57.3 (CH3),
54.8 (CH3), 54.3 (C), 42.1 (CH2), 38.3 (CH3), 36.0 (CH3). νmax
(KBr)/cm−1 3511, 3391, 2910, 2889, 1608, 1581, 1479, 1408,
0.6, CHCl3) [Found: M+•, 394.1993. C21H30O7 requires M+•
,
394.1992]. δH (300 MHz) 7.02 (t, J 8.2, 1H), 6.88–6.81 (com-
plex m, 2H), 5.90 (d, J 3.2, 1H), 5.34 (d, J 5.8, 1H), 4.83 (dd,

Chemoenzymatic Synthesis of (+)-Galanthamine
1443
1297, 1198, 1180, 1132, 1088, 1020, 986, 938, 894, 840, 815,
739. m/z (ESI, +ve ion) 520 [(M + Na)+, 52%], 518 (100),
516 (50), 496 (11).
pressure and the residue so obtained subjected to flash chro-
matography (silica, 1:1:8 v/v/v methanol/hexane/ethyl acetate
elution). Concentration of the appropriate fractions (RF 0.4 in
1:1:8 v/v/v methanol/hexane/ethyl acetate) then gave benzofu-
ran 15 (896 mg, 68%) as a white, crystalline solid, mp 76–79◦C,
[α]D +25.0 (c 0.5, CHCl3) [Found: M+•, 377.1835. C20H27NO6
requires M+•, 377.1838]. δH (300 MHz) 7.06 (dd, J 6.8 and 1.8,
1H), 6.76 (m, 2H), 5.13 (t, J 3.8, 1H), 4.90 (d, J 8.3, 1H), 4.24 (t,
J 6.8, 1H), 3.83 (s, 3H), 3.79 (m, 1H), 3.00 (d, J 7.1, 1H), 2.91
(s, 3H), 2.90 (s, 3H), 2.67 (br s, 1H), 2.52 (d, J 7.1, 1H), 2.20–
2.03 (complex m, 2H), 1.38 (s, 3H), 1.31 (s, 3H). δC (75 MHz)
170.2 (C), 147.7 (C), 143.9 (C), 131.7 (C), 120.3 (CH), 120.1
(CH), 111.4 (CH), 108.8 (C), 85.9 (CH), 80.8 (CH), 76.8 (CH),
67.2 (CH), 55.9 (CH3), 49.6 (C), 43.3 (CH2), 37.3 (CH3), 35.4
(CH3), 35.0 (CH2), 25.7 (CH3), 24.3 (CH3). νmax (KBr)/cm−1
3428, 2984, 2938, 1637, 1491 1460, 1401, 1381, 1272, 1208,
1074, 996, 868, 735. m/z (EI, 70 eV) 377 (M+•, 30%), 362
(39), 319 (12), 301 (21), 290 (45), 272 (25), 233 (67), 215 (84),
204 (63), 175 (100), 161 (65), 115 (25).
Compound 13
A magnetically stirred mixture of compound 12 (722 mg,
1.458 mmol), 10% Pd/C (90 mg), anhydrous potassium carbon-
ate (1.0 g, 7.2 mmol), and methanol (5 mL) was exposed to a
balloon of hydrogen gas. After stirring at 18◦C for 18 h, the
reaction mixture was purged with nitrogen and then filtered
through a short pad of Celite.The filtrate was concentrated under
reduced pressure and the residue so obtained was subjected to
flash chromatography (silica, 1:3 v/v methanol/ethyl acetate elu-
tion). Concentration of the relevant fractions (RF 0.5 in 1:3 v/v
methanol/ethyl acetate) then gave 7-oxanorbornene 13 (329 mg,
67%) as a white, crystalline solid, mp 214–217◦C, [α]D +155.0
(c 0.4, CH3OH) [Found: (M + Na)+, 358.1272. C17H21NO6
requires (M + Na)+, 358.1267]. δH (300 MHz, CD3OD) 6.93
(dd, J 6.8 and 1.7, 1H), 6.76 (dd, J 8.1 and 1.7, 1H), 6.74 (dd, J
8.1 and 6.8, 1H), 5.10 (s, 1H), 4.61 (t, J 1.2, 1H), 5.21 (dd, J 5.6
and 1.2, 1H), 4.02 (dt, J 5.6 and 1.0, 1H), 3.90 (d, J 1.0, 1H),
3.80 (s, 3H), 3.06 (d, J 5.6, 2H), 2.98 (s, 3H), 2.93 (s, 3H). δC
(75 MHz, CD3OD) 172.4 (C), 151.3 (C), 145.3 (C), 133.9 (C),
122.2 (CH), 117.5 (CH), 113.5 (CH), 92.9 (CH), 90.5 (CH), 85.0
(CH), 80.4 (CH), 78.3 (CH), 58.2 (C), 56.5 (CH3), 38.8 (CH2),
38.0 (CH3), 35.8 (CH3). νmax (KBr)/cm−1 3385, 2929, 2840,
1625, 1491, 1460, 1272, 1200, 1133, 1099, 1063, 1036, 980,
739. m/z (ESI, +ve ion) 358 [(M + Na)+, 100%], 336 (3).
Compound 16
DMAP (18 mg, 0.147 mmol) was added to a magnetically
stirred solution of compound 15 (961 mg, 2.55 mmol) and acetic
anhydride (0.8 mL, 8.46 mmol) in pyridine (20 mL). After stir-
ring at 18◦C for 2 h, the reaction mixture was concentrated under
reduced pressure and the residue so obtained was subjected to
flash chromatography (silica, 1:1:8 v/v/v methanol/hexane/ethyl
acetate elution). Concentration of the appropriate fractions (RF
0.4 in 1:5:6 v/v/v methanol/hexane/ethyl acetate) then gave the
acetate 16 (961 mg, 90%) as a white, crystalline solid, mp
75–78◦C, [α]D +41.2 (c 0.5, CHCl3) [Found: M+•, 419.1939.
C22H29NO7 requires M+•, 419.1944]. δH (300 MHz) 7.06 (t, J
4.6, 1H), 6.76 (m, 2H), 5.12 (t, J 3.7, 1H), 5.01 (d, J 8.1, 1H),
4.91 (ddd, J 12.0, 7.1, and 3.2, 1H), 4.39 (dd, J 8.1 and 7.1,
1H), 3.88 (s, 3H), 3.05 (d, J 16.8, 1H), 2.98 (s, 3H), 2.90 (s,
3H), 2.54 (d, J 16.8, 1H), 2.32 (dt, J 13.9 and 3.2, 1H), 2.09 (m,
1H), 2.02 (s, 3H), 1.42 (s, 3H), 1.33 (s, 3H). δC (75 MHz) 170.2
(C), 169.8 (C), 148.2 (C), 144.2 (C), 131.2 (C), 120.3 (CH),
120.2 (CH), 112.8 (CH), 109.2 (C), 85.7 (CH), 77.7 (CH), 76.5
(CH), 70.0 (CH), 56.8 (CH3), 49.5 (C), 42.9 (CH2), 37.4 (CH3),
35.4 (CH3), 32.6 (CH2), 25.8 (CH3), 24.4 (CH3), 21.4 (CH3).
νmax (KBr)/cm−1 2982, 2938, 1743, 1642, 1491, 1460, 1380,
Compound 14
Molecular bromine (2.2 mL, 43.0 mmol) was added to a mag-
netically stirred solution of compound 11 (4.0 g, 8.6 mmol) in
toluene (150 mL) maintained at 18◦C. After 18 h the reaction
mixture was treated with acetone (100 mL) and stirring contin-
ued for a further 2 h.The reaction mixture was then concentrated
underreducedpressureandtheensuingresiduesubjectedtoflash
chromatography (silica, 1:8:12 v/v/v methanol/hexane/ethyl
acetate elution). Concentration of the relevant fractions (RF
0.4 in 1:5:6 v/v/v methanol/hexane/ethyl acetate) provided the
dibromoacetonide 14 (4.3 g, 93%) as a white, crystalline solid,
mp 145–149◦C, [α]D +79.0 (c 0.5, CHCl3) [Found: (M –
CH3•)+, 521.9780. C19H2281Br2NO6 requires (M – CH3•)+,
521.9773]. δH (300 MHz) 7.03 (d, J 1.7, 1H), 6.87 (d, J 1.7, 1H),
5.21 (d, J 7.8, 1H), 4.92 (d, J 6.6, 1H), 4.56 (m, 2H), 3.98 (br s,
1H), 3.86 (s, 3H), 2.93 (s, 3H), 2.89 (s, 3H), 2.85 (d, J 5.6, 2H),
1.57 (br s, 1H), 1.34 (s, 3H), 1.31 (s, 3H). δC (75 MHz) 169.4 (C),
146.2 (C), 145.0 (C), 132.7 (C), 121.0 (CH), 115.2 (CH), 112.3
(C), 108.9 (C), 89.8 (CH), 77.8 (CH), 76.5 (CH), 56.3 (CH), 53.7
(CH3), 51.3 (C), 42.3 (CH2), 37.7 (CH3), 35.8 (CH3), 26.6 (CH),
24.4(2 × CH3). νmax (KBr)/cm−1 3368, 2988, 2936, 1622, 1487,
1263, 1209, 1052, 995, 909, 730. m/z (EI, 70 eV) 522, 520, and
518 [(M – CH3•)+, 12, 7, and 7%], 438 and 436 (31 and 29),
380 and 378 (both 60), 307 and 305 (29 and 27), 227 (12), 115
(11), 87 (72), 72 (100), 49 (65).
1273, 1237, 1209, 1078, 1047, 735. m/z (EI, 70 eV) 419 (M+•
,
14%), 404 (12), 302 (13), 272 (16), 215 (38), 214 (23), 175 (15),
87 (100), 72 (41), 57 (5), 43 (35).
Compound 17
Step i: Acetate 16 (734 mg, 1.750 mmol) was dissolved in
acetic acid/water (30 mL of a ∼2:1 v/v mixture) and the result-
ing solution stirred at 18◦C for 20 h and then concentrated under
reducedpressure. Subjectionoftheensuingresiduetoflashchro-
matography (silica, 1:1:8 v/v/v methanol/hexane/ethyl acetate
elution) afforded, after concentration of the appropriate fractions
(RF 0.4 in 1:1:8 v/v/v methanol/hexane/ethyl acetate), the diol
precursor to compound 17 (628 mg, 94%) as a white, crystalline
solid, mp 129–131◦C, [α]D +86.0 (c 0.5, CHCl3) [Found: M+•
,
Compound 15
A magnetically stirred mixture of compound 14 (1.87 g,
3.49 mmol), 10% Pd/C (318 mg), potassium carbonate (434 mg,
3.14 mmol), and methanol (6 mL) was exposed to a balloon
of hydrogen gas. After stirring at 18◦C for 18 h, the reaction
mixture was purged with nitrogen and then filtered through a
short pad of Celite. The filtrate was concentrated under reduced
379.1630. C19H25NO7 requires M+•, 379.1631]. δH (300 MHz)
7.08 (dd, J 7.3 and 1.2, 1H), 6.80 (m, 2H), 4.95 (m, 2H), 4.45 (d,
J 4.6, 1H), 4.00 (t, J 4.0, 1H), 3.86 (s, 3H), 3.33 (d, J 15.3, 1H),
2.93 (d, J 5.6, 1H), 2.88 (s, 3H), 2.71 (s, 3H), 2.45 (d, J 15.3,
1H), 2.28–2.18 (complex m, 2H), 2.08 (s, 3H), 1.60 (br s, 1H). δC
(75 MHz) 171.6 (C), 171.4 (C), 146.7 (C), 145.0 (C), 132.0 (C),

1444
M. G. Banwell et al.
121.6 (CH), 118.4 (CH), 111.8 (CH), 86.2 (CH), 73.6 (CH), 71.7
(CH), 71.5 (CH), 56.0 (CH3), 50.1 (C), 42.2 (CH2), 37.8 (CH3),
35.8 (CH3), 28.3 (CH2), 21.2 (CH3). νmax (KBr)/cm−1 3393,
2938, 2837, 1732, 1620, 1491, 1458, 1247, 1044, 740. m/z (EI,
70 eV) 379 (M+•, 24%), 361 (2), 292 (4), 232 (22), 215 (36),
175 (14), 161 (16), 87 (100), 72 (47), 57 (11), 45 (37), 43 (33).
Step ii: A solution of the diol (628 mg, 1.655 mmol), pre-
pared as described immediately above, and DMAP (910 mg,
7.449 mmol) in dry dichloromethane (20 mL) maintained at
0◦C (ice-bath) under a nitrogen atmosphere was treated, drop-
wise, with thiophosgene (189 μL, 2.479 mmol). After stirring
at 0◦C for 1 h, the reaction mixture was treated with methanol
(2 mL) and then concentrated under reduced pressure. Subjec-
tion of the ensuing residue to flash chromatography (silica,
1:4:6 v/v/v methanol/hexane/ethyl acetate elution) and con-
centration of the appropriate fractions (RF 0.5 in 1:3:6 v/v/v
methanol/hexane/ethyl acetate) afforded compound 17 (691 mg,
99%) as a white, crystalline solid, mp 122–124◦C, [α]D −25.0
(c 0.5, CHCl3) [Found: M+•, 421.1198. C20H23NO7S requires
(3 × 20 mL) and the combined organic phases were then dried
(MgSO4), filtered, and concentrated under reduced pressure.The
resulting light-yellow oil was subjected to flash chromatography
(silica, 1:1:8 v/v/v methanol/hexane/ethyl acetate elution) and
gave, after concentration of the appropriate fractions (RF 0.4 in
1:1:8 v/v/v methanol/hexane/ethyl acetate), the allylic alcohol
19 (338 mg, 95%) as a white, crystalline solid, mp 163–166◦C,
[α]D +10.0 (c 0.5, CHCl3) [Found: (M + Na)+, 326.1365.
C17H21NO4 requires (M + Na)+, 326.1368]. δH (300 MHz)
6.89–6.82 (complex m, 1H), 6.80–6.73 (complex m, 2H), 6.12
(dd, J 9.8 and 5.5, 1H), 5.86 (d, J 9.8, 1H), 5.42 (dd, J 10.3
and 5.5, 1H), 4.19 (m, 1H), 3.87 (s, 3H), 3.28 (br s, 1H),
2.93 (s, 6H), 2.70 (s, 2H), 2.42 (m, 1H), 1.84 (m, 1H). δC
(75 MHz) 170.0 (C), 146.3 (C), 145.6 (C), 133.8 (C), 130.2
(CH), 129.8 (CH), 121.6 (CH), 115.2 (CH), 111.8 (CH), 84.1
(CH), 63.2 (CH), 56.1 (CH3), 47.8 (C), 42.6 (CH2), 37.3 (CH3),
35.6 (CH3), 35.2 (CH2). νmax (KBr)/cm−1 3391, 2937, 2838,
1623, 1592, 1491, 1458, 1400, 1278, 1201, 1046. m/z (ESI) 326
[(M + Na)+, 100%], 286 (10).
M
+•, 421.1195]. δH (300 MHz) 7.06 (dd, J 6.7 and 2.1, 1H),
Compound 20
6.83 (m, 2H), 5.95 (d, J 8.9, 1H), 5.15–5.02 (complex m, 3H),
3.87 (s, 3H), 3.13 (d, J 17.6, 1H), 2.93(4) (s, 3H), 2.93(0) (s,
3H), 2.62 (d, J 17.6, 1H), 2.38 (dt, J 14.0 and 2.8, 1H), 2.11 (m,
1H), 2.01 (s, 3H). δC (75 MHz) 190.7 (C), 169.4 (C), 169.2 (C),
148.2 (C), 144.5 (C), 127.4 (C), 122.4 (CH), 118.4 (CH), 114.0
(CH), 84.7 (CH), 84.1 (CH), 82.1 (CH), 66.9 (CH), 56.5 (CH3),
48.8 (C), 41.7 (CH2), 37.2 (CH3), 35.4 (CH3), 32.1 (CH2), 21.0
(CH3). νmax (KBr)/cm−1 2937, 2838, 1749, 1639, 1492, 1286,
1230, 1049, 982, 734. m/z (EI, 70 eV) 421 (M+•, 6%), 408 (10),
365 (5), 361 (4), 229 (10), 215 (50), 149 (24), 105 (33), 87 (100),
84 (38), 72 (37), 57 (60), 43 (77).
tert-Butylchlorodiphenylsilane (184 μL, 0.72 mmol) was
added to a magnetically stirred solution of allylic alcohol 19
(136 mg, 0.45 mmol) and imidazole (155 mg, 2.28 mmol) in dry
dichloromethane (15 mL) maintained at 18◦C under a nitrogen
atmosphere. After 18 h the reaction mixture was poured into
brine (50 mL of a saturated aqueous solution) and the separated
aqueous phase was extracted with dichloromethane (1 × 25 mL).
The combined organic phases were then dried (MgSO4), fil-
tered, and concentrated under reduced pressure. Subjection of
the ensuing crude material to flash chromatography (silica, 1:1
v/v hexane/ethyl acetate elution) afforded, after concentration
of the appropriate fractions (RF 0.5 in 8:2.5:5.5 v/v/v ethyl
acetate/dichloromethane/hexane), theTBDPS-ether 20 (231 mg,
95%) as a clear, colourless oil, [α]D +107.2 (c 0.5, CHCl3)
[Found: (M – C4H9•)+, 484.1943. C33H39NO4Si requires (M –
C4H9•)+, 484.1944]. δH (300 MHz) 7.69–7.60 (complex m, 4H),
7.44–7.31 (complex m, 6H), 6.82 (dd, J 7.6 and 1.7, 1H), 6.77
(t, J 7.6, 1H), 6.69 (dd, J 7.6 and 1.7, 1H), 5.81 (dd, J 10.2 and
1.0, 1H), 5.73 (dd, J 10.2 and 2.7, 1H), 4.99 (t, J 4.2, 1H), 4.48
(m, 1H), 3.79 (s, 3H), 2.97 (d, J 14.6, 1H), 2.94 (s, 3H), 2.92 (s,
3H), 2.68 (d, J 14.6, 1H), 2.42 (dt, J 13.7 and 5.4, 1H), 2.09 (m,
1H), 1.05 (s, 9H). δC (75 MHz) 169.7 (C), 147.0 (C), 144.8 (C),
135.9(4) (2 × CH), 135.9(1) (2 × CH), 134.3 (C), 134.2(5) (C),
134.1(9) (C), 131.6 (CH), 129.8 (CH), 129.7 (2 × CH), 127.7(4)
(2 × CH), 127.7(1) (2 × CH), 121.4 (CH), 116.1 (CH), 111.7
(CH), 86.2 (CH), 64.3 (CH), 56.1 (CH3), 47.4 (C), 41.4 (CH2),
38.2 (CH3), 35.6 (CH3), 33.6 (CH2), 27.1 (3 × CH3), 19.3 (C).
νmax (KBr)/cm−1 3070, 2932, 2857, 1650, 1590, 1490, 1460,
1390, 1284, 1203, 1100, 1090. m/z (EI, 70 eV) 541 (M+•, 3%),
484 [(M – C4H9•)+, 17], 397 (4), 286 (40), 199 (100), 135 (8),
87 (88), 57 (16).
Compound 18
A magnetically stirred solution of thiocarbonate 17 (691 mg,
1.640 mmol) in trimethylphosphite/toluene (40 mL of a 1:1
v/v mixture) was heated at reflux for 18 h and then cooled
and concentrated under reduced pressure. Subjection of the
ensuing residue to flash chromatography (silica, 1:4:5 v/v/v
methanol/hexane/ethyl acetate elution) afforded, after concen-
tration of the appropriate fractions (RF 0.4 in 1:4:6 v/v/v
methanol/hexane/ethyl acetate), compound 18 (407 mg, 72%) as
a clear, colourless oil, [α]D +131.0 (c 0.5, CHCl3) [Found: M+•
,
345.1577. C19H23NO5 requires M+•, 345.1576]. δH (300 MHz)
6.85–6.72 (complex m, 3H), 5.92 (d, J 10.0, 1H), 5.78 (d, J 10.0,
1H), 5.42 (m, 1H), 5.04 (t, J 4.1, 1H), 3.86 (s, 3H), 3.02 (d,
J 15.8, 1H), 2.95 (s, 3H), 2.92 (s, 3H), 2.71 (d, J 15.8, 1H),
2.55 (m, 1H), 2.25 (m, 1H), 2.05 (s, 3H). δC (75 MHz) 170.6
(C), 169.5 (C), 146.7 (C), 144.9 (C), 134.0 (C), 132.1 (CH),
127.4 (CH), 121.6 (CH), 115.7 (CH), 111.7 (CH), 85.6 (CH),
66.0 (CH), 56.0 (CH3), 47.5 (C), 41.7 (CH2), 38.0 (CH3), 35.6
(CH3), 30.1 (CH2), 21.3 (CH3). νmax (KBr)/cm−1 2938, 2836,
1732, 1648, 1492, 1459, 1278, 1242, 1204, 1031, 732. m/z (EI,
70 eV) 345 (M+•, 6%), 244 (3), 199 (24), 198 (21), 128 (4),
87 (100), 72 (26), 45 (26), 43 (27).
Compound 21
A magnetically stirred solution of TBDPS-ether 20 (218 mg,
0.40 mmol) in dry THF (20 mL) maintained at 18◦C under a
nitrogen atmosphere was treated, dropwise, with Superhydride
(2.0 mL of a 1.0 M solution in THF, 2.0 mmol). After 4 h the
reaction mixture was quenched with methanol (1.0 mL) and
then concentrated under reduced pressure. Subjection of the
ensuing light-yellow oil to flash chromatography (silica, 7:10
v/v ethyl acetate/hexane elution) afforded, after concentration
of the appropriate fractions (RF 0.3 in 2:2.5:5.5 v/v/v ethyl
Compound 19
Potassium carbonate (244 mg, 1.765 mmol) was added to
a magnetically stirred solution of allylic acetate 18 (407 mg,
1.178 mmol) in methanol (8 mL) maintained at 18◦C. After
1 h the reaction mixture was concentrated under reduced pres-
sure and the residue so-obtained was treated with ethyl acetate
(40 mL) and NaHCO3 (60 mL of a saturated aqueous solution).
The separated aqueous phase was extracted with ethyl acetate

Chemoenzymatic Synthesis of (+)-Galanthamine
1445
acetate/dichloromethane/hexane), compound 21 (191 mg, 95%)
2.76 (d, J 4.8, 3H), 2.64 (d, J 4.8, 2H), 2.48 (m, 1H), 1.97 (m,
1H), 1.07 (s, 9H). δC (75 MHz) 170.0 (C), 146.9 (C), 144.9
(C), 135.9 (4 × CH), 134.2 (C), 134.0 (C), 133.8 (C), 132.3
(CH), 129.8 (CH), 129.7 (CH), 129.3 (CH), 127.7(6) (2 × CH),
127.7(3) (2 × CH), 121.6 (CH), 115.3 (CH), 112.0 (CH), 85.4
(CH), 64.1 (CH), 56.0 (CH3), 47.0 (C), 45.2 (CH2), 33.1 (CH2),
27.0 (3 × CH3), 26.4 (CH3), 19.3 (C). νmax (KBr)/cm−1 3310,
3071, 2932, 2858, 1644, 1590, 1492, 1460, 1278, 1204, 111,
1090, 909, 864, 733, 702. m/z (EI, 70 eV) 527 (M+•, 3%),
470 (45), 397 (4), 272 (26), 199 (100), 135 (11), 73 (44), 57 (28),
43 (19).
as a white foam, [α]D +101.0 (c 0.5, CHCl3) [Found: M+•
,
500.2382. C31H36O4Si requires M+•, 500.2383]. δH (300 MHz)
7.72–7.67 (complex m, 4H), 7.46–7.34 (complex m, 6H), 6.82
(dd, J 8.2 and 7.2, 1H), 6.70 (dm, J 4.2, 2H), 5.80 (dd, J 10.2 and
2.9, 1H), 5.60 (d, J 10.2, 1H), 5.02 (m, 1H), 4.50 (m, 1H), 3.82 (s,
3H), 3.78(t, J6.6, 2H), 2.33(dt, J13.8and5.5, 1H), 2.01(m, 3H),
1.80 (br s, 1H), 1.09 (s, 9H). δC (75 MHz) 146.8 (C), 144.9 (C),
135.9 (4 × CH), 134.6 (C), 134.1 (C), 134.0 (C), 131.3 (CH),
130.8 (CH), 129.9 (CH), 129.8 (CH), 127.8 (2 × CH), 127.7
(2 × CH), 121.5 (CH), 115.2 (CH), 111.6 (CH), 85.2 (CH), 64.4
(CH), 59.6 (CH2), 56.0 (CH3), 47.7 (C), 41.2 (CH2), 34.0 (CH2),
27.0 (3 × CH3), 19.2 (C). νmax (KBr)/cm−1 3436, 3070, 2931,
2893, 2857, 1618, 1590, 1492, 1459, 1427, 1280, 1203, 1111,
1083, 1029. m/z (EI, 70 eV) 500 (M+•, 7%), 443 (13), 365 (10),
244 (27), 227 (51), 199 (100), 139 (14).
Compound 23
A magnetically stirred solution of amide 22 (131 mg,
0.248 mmol) in THF (10 mL) was treated with TBAF (0.4 mL
of 1.0 M solution in THF, 0.4 mmol) and then stirred at 18◦C
for 30 h. The resulting mixture was concentrated under reduced
pressure and the light-yellow oil so-obtained was subjected to
flash chromatography (silica, 3:20 v/v methanol/ethyl acetate
elution). Concentration of the appropriate fractions (RF 0.4 in
1:9 v/v methanol/ethyl acetate) then gave alcohol 23 (61 mg,
85%) as a white, crystalline solid, mp 233–236◦C, [α]D +142.0
(c 0.2, CH3OH) [Found: M+•, 289.1313. C16H19NO4 requires
Compound 22
Step i:A magnetically stirred solution of alcohol 21 (181 mg,
0.361 mmol) in dry dichloromethane (15 mL) maintained at
18◦C was treated with the Dess–Martin periodinane (184 mg,
0.434 mmol).After16 hthereactionmixturewasfilteredthrough
a short pad of Celite and the filtrate concentrated under reduced
pressure. Subjection of the resulting light-yellow to flash
chromatography (silica, 3:5 v/v ethyl acetate/hexane elution)
afforded, after concentration of the appropriate fractions (RF
0.5 in 1:2.5:5.5 v/v/v ethyl acetate/dichloromethane/hexane),
the aldehydic precursor to compound 22 (177 mg, 98%) as a
M
+•, 289.1314]. δH (300 MHz) 6.85 (t, J 7.0, 1H), 6.76 (d, J 7.0,
1H), 6.73 (dd, J 7.0 and 1.2, 1H), 6.05 (dd, J 10.0 and 4.7, 1H),
5.79 (d, J 10.0, 1H), 5.51 (br s, 1H), 5.40 (dd, J 8.2 and 4.7, 1H),
4.30 (br s, 1H), 3.87 (s, 3H), 3.22 (br s, 1H), 2.78 (d, J 4.7, 3H),
2.71 (d, J 15.2, 1H), 2.50 (d, J 15.2, 1H), 2.24 (m, 1H), 2.12
(m, 1H). δC (75 MHz) 172.8, 148.1, 146.0, 135.6, 133.0, 131.4,
122.6, 116.7, 113.5, 86.6, 63.0, 56.6, 45.2, 34.1, 30.8, 26.2. νmax
(KBr)/cm−1 3306, 2941, 2836, 1650, 1619, 1592, 1491, 1459,
1280, 1201, 1043, 742. m/z (EI, 70 eV) 289 (M+•, 5%), 271 (3),
240 (6), 216 (75), 199 (63), 188 (15), 115 (10), 73 (100), 57 (18),
43 (17).
clear, light-yellow oil, [α]D +123.0 (c 0.5, CHCl3) [Found: M+•
,
498.2213. C31H34O4Si requires M+•, 498.2226]. δH (300 MHz)
9.79 (t, J 2.7, 1H), 7.70–7.65 (complex m, 4H), 7.46–7.33 (com-
plex m, 6H), 6.84 (m, 1H), 6.72 (m, 2H), 5.79 (dd, J 10.2 and
2.2, 1H), 5.65 (dd, J 10.2 and 2.2, 1H), 4.89 (t, J 4.4, 1H), 4.52
(m, 1H), 3.82 (s, 3H), 2.80 (dd, J 2.7 and 1.7, 2H), 2.40 (dt, J
13.5 and 5.1, 1H), 1.99 (dddd, J 11.7, 8.1, 4.6, and 3.1, 1H),
1.07 (s, 9H). δC (75 MHz) 200.8 (CH), 146.9 (C), 145.1 (C),
135.9 (2 × CH), 135.8(8) (2 × CH), 134.0 (C), 133.9 (C), 132.9
(C), 132.2 (CH), 129.9 (CH), 129.8 (CH), 128.9 (CH), 127.8
(2 × CH), 127.7(7) (2 × CH), 122.0 (CH), 115.3 (CH), 112.0
(CH), 85.2 (CH), 64.0 (CH), 56.1 (CH3), 51.3 (C), 46.8 (CH2),
33.2 (CH2), 27.0 (3 × CH3), 19.3 (C). νmax (KBr)/cm−1 3069,
2931, 2857, 1722, 1617, 1590, 1492, 1458, 1286, 1203, 1111,
1086, 1035, 864, 702. m/z (EI, 70 eV) 498 (M+•, 3%), 441 (11),
225 (8), 199 (100), 165 (18), 139 (37), 105 (9), 84 (11), 57 (15).
Step ii: NBS (119 mg, 0.669 mmol) and AIBN (11 mg,
0.067 mmol) were added to a magnetically stirred solution of
the above-mentioned aldehyde (167 mg, 0.335 mmol) in dry car-
bon tetrachloride (20 mL) and the ensuing mixture was placed
in a pre-heated oil-bath maintained at 95◦C. After 0.75 h the
reaction mixture was cooled, placed in an ice-bath (0◦C), and
then treated with methylamine (1.0 mL of a 2.0 M solution
in THF). After being stirred at 0◦C for 1 h the reaction mix-
ture was concentrated under reduced pressure and the residue
so obtained was subjected to flash chromatography (silica,
1:3:7 v/v/v methanol/hexane/ethyl acetate elution). Concentra-
tion of the appropriate fractions (RF 0.4 in 8:2.5:5.5 v/v/v
ethyl acetate/dichloromethane/hexane) then gave compound 22
(141 mg, 80%) as a white, crystalline solid, mp 56–60◦C, [α]D
+87.6 (c 0.5, CHCl3) [Found: M+•, 527.2481. C32H37NO4Si
requires M+•, 527.2492]. δH (300 MHz) 7.69–7.62 (complex m,
4H), 7.45–7.31 (complex m, 6H), 6.83–6.68 (complex m, 3H),
5.74 (dd, J 10.1 and 1.7, 1H), 5.62 (dd, J 10.1 and 1.2, 1H),
5.51 (m, 1H), 4.96 (t, J 3.7, 1H), 4.52 (m, 1H), 3.80 (s, 3H),
Compound 24
A magnetically stirred solution of compound 23 (50 mg,
0.173 mmol), paraformaldehyde (30 mg, 0.990 mmol), and
trifluoroacetic acid (266 μL, 3.453 mmol) in dry 1,2-
dichloroethane (15 mL) was heated at 60◦C for 48 h and then
cooled and concentrated under reduced pressure. The residue
thus obtained was dissolved in methanol (5 mL) and the result-
ing solution treated with triethylamine (2 mL). After 2 h the
reaction mixture was concentrated under reduced pressure and
the resulting light-yellow oil subjected to flash chromato-
graphy (silica, 1:10 v/v methanol/chloroform elution). Con-
centration of the appropriate fractions (RF 0.4 in 1:1:9 v/v/v
methanol/hexane/ethyl acetate) then gave lactam 24 (46 mg,
88%) as a white, crystalline solid, mp 232–235◦C, [α]D +223.0
(c 0.2, CHCl3) [Found: (M + H)+, 302.1389. C17H19NO4
requires (M + H)+, 302.1392]. δH (300 MHz) 6.66 (m, 2H), 5.84
(dd, J 10.0 and 1.8, 1H), 5.45 (dt, J 10.0 and 1.8, 1H), 4.69–
4.60 (complex m, 2H), 4.50 (d, J 15.8, 1H), 4.23 (d, J 15.8,
1H), 3.85 (s, 3H), 2.98 (s, 3H), 2.94–2.74 (m, 3H), 2.01 (br s,
1H), 1.80 (m, 1H). δC (75 MHz) 171.3 (C), 147.8 (C), 144.8
(C), 131.9 (CH), 131.7 (C), 129.0 (CH), 125.5 (C), 119.6 (CH),
111.8 (CH), 87.7 (CH), 62.8 (CH), 56.2 (CH3), 52.2 (C), 43.5
(CH2), 42.9 (CH2), 35.8 (CH3), 31.2 (CH2). νmax (KBr)/cm−1
3408, 2922, 1632, 1508, 1435, 1342, 1282, 1103, 1050, 1037,
802, 732. m/z (EI, 70 eV) 302 [(M + H)+, 54%], 301 (100),
230 (35), 229 (33), 197 (26), 174 (22), 115 (16), 85 (29), 71 (37),
57 (56), 43 (42).

1446
M. G. Banwell et al.
Compound 25
Compound C8a-epi-11
A magnetically stirred solution of lactam 24 (46 mg,
0.153 mmol) in toluene (10 mL) maintained at 18◦C was treated
with chloroacetic acid (43 mg, 0.455 mmol), triphenylphos-
phine (140 mg, 0.554 mmol), and diisopropyl azodicarboxylate
(75 μL, 0.381 mmol).After 18 h the reaction mixture was diluted
with ethyl acetate (50 mL) and then treated with NaHCO3
(50 mL of a saturated aqueous solution). The separated aque-
ous phase was extracted with ethyl acetate (2 × 15 mL) and the
combined organic phases were then dried (MgSO4), filtered,
and concentrated under reduced pressure. The ensuing light-
yellow oil was subjected to flash chromatography (silica, 1:4:5
v/v/v methanol/ethyl acetate/hexane elution) to give, after con-
centration of the appropriate fractions (RF 0.5 in 1:1:8 v/v/v
methanol/hexane/ethyl acetate), chloroacetate 25 (54 mg, 93%)
as a white, crystalline solid, mp 55–58◦C, [α]D +80.5 (c 0.2,
A magnetically stirred solution of compound 9 (541 mg,
1.37 mmol) in toluene (20 mL) was treated with N,N-
dimethylacetamide dimethyl acetal (2.5 mL, 15.4 mmol) and the
ensuing mixture heated (oil bath) at reflux. When TLC anal-
ysis indicated that no starting material remained (∼28 days),
the reaction mixture was cooled and then concentrated under
reduced pressure. Subjection of the ensuing residue to flash
chromatography (silica, 1:10:40 v/v/v methanol/hexane/ethyl
acetate elution) and concentration of the appropriate fractions
(RF 0.3 in 8:2.5:5.5 v/v/v ethyl acetate/dichloromethane/hexane)
afforded amide C8a-epi-11 (238 mg, 37%) as a clear, colour-
less oil, [α]D −16.8 (c 1.0, CHCl3) [Found: M+•, 463.2573.
C25H37NO7 requires M+•, 463.2570]. δH (300 MHz) 6.88 (t, J
8.0, 1H), 6.77 (dd, J 8.0 and 1.5, 1H), 6.71 (dd, J 8.0 and 1.5,
1H), 6.52 (dd, J 10.2 and 2.5, 1H), 5.66 (dd, J 10.2 and 2.2, 1H),
5.16 (sept, J 6.2, 1H), 4.86 (d, J 6.6, 1H), 4.72 (d, J 7.1, 2H), 4.32
(m, 1H), 4.22 (dd, J 7.6 and 4.8, 1H), 3.77 (s, 3H), 3.53 (d, J 17.3,
1H), 3.39 (s, 3H), 3.04 (s, 3H), 2.85 (s, 3H), 2.51 (d, J 17.3, 1H),
1.47 (s, 3H), 1.30 (s, 3H), 1.26 (d, J 6.2, 3H), 1.21 (d, J 6.2, 3H).
δC (75 MHz) 170.7 (C), 152.3 (C), 143.7 (C), 139.4 (CH), 137.2
(C), 122.2 (CH), 121.6 (CH), 121.0 (CH), 111.5 (CH), 108.0
(C), 95.3 (CH2), 80.0 (CH), 79.5 (CH), 74.4 (CH), 72.9 (CH),
55.7 (CH3), 55.4 (CH3), 45.1 (C), 37.9 (CH2), 37.5 (NCH3),
35.4 (NCH3), 27.0 (CH3), 24.9 (CH3), 22.7 (CH3), 22.0 (CH3).
νmax (KBr)/cm−1 2982, 2935, 1659, 1580, 1454, 1393, 1381,
CHCl3) [Found: M+•, 377.1033. C19H2035ClNO5 requires M+•
,
377.1030]. δH (300 MHz) 6.90 (ABq, J 13.5, 2H), 5.92 (dd, J
10.0 and 5.9, 1H), 5.22 (dd, J 10.0 and 1.2, 1H), 5.43 (t, J 4.7,
1H), 4.66 (s, 1H), 4.48 (d, J 16.4, 1H), 4.33 (d, J 16.4, 1H),
4.09 (ABq, J 8.2, 1H), 3.86 (s, 3H), 3.02 (s, 3H), 2.88–2.45
(complex m, 3H), 2.22 (dm, J 5.7, 1H). δC (75 MHz) 170.9
(C), 167.3 (C), 147.4 (C), 144.9 (C), 132.9 (CH), 131.0 (C),
125.2 (C), 122.6 (CH), 119.7 (CH), 112.5 (CH), 85.5 (CH), 65.0
(CH), 56.3 (CH3), 52.2 (C), 43.1 (CH2), 42.1 (CH2), 41.4 (CH2),
36.1 (CH3), 26.7 (CH2). νmax (KBr)/cm−1 2956, 2930, 1748,
1648, 1508, 1438, 1284, 1190, 1072, 1025, 730. m/z (EI, 70 eV)
379 and 377 (M+•, 34 and 100%), 308 and 306 (4 and 10),
240 (15), 211 (41), 165 (12), 115 (9), 85 (18), 71 (25), 57 (37),
43 (27).
1263, 1151, 1104, 1056, 919, 761. m/z (EI, 70 eV) 463 (M+•
,
12%), 402 (14), 87 (59), 73 (46), 72 (63), 59 (36), 45 (100),
43 (77).
X-ray Crystallographic Studies
Crystal Data for Compound 12
(+)-Galanthamine [(+)-1]
C17H21Br2NO6, M 495.16, T 200 K, monoclinic, space
group P21, Z 2, a 8.1312(2), b 7.1811(1), c 16.7998(4) Å, β
103.2724(10)◦, V 954.75(4) Å3, Dx 1.722 g cm−3, 4351 unique
data (2θmax 55◦), R 0.024 [for 3770 reflections with I > 2.0σ(I)];
Rw 0.062 (all data), S 0.90, Flack parameter −0.02(1).
A magnetically stirred solution of chloroacetate 25 (34 mg,
0.090 mmol) in dry THF (10 mL) maintained under a nitrogen
atmosphere was treated with lithium aluminum hydride (0.5 mL
of a 1.0 M solution in THF, 0.5 mmol). After stirring at 18◦C
for 4 h the reaction mixture was treated with methanol (2 mL)
and then NaHCO3 (40 mL of a saturated aqueous solution).
The separated aqueous phase was extracted with chloroform
(4 × 15 mL) and the combined organic phases were then dried
(MgSO4), filtered, and concentrated under reduced pressure.
Subjection of the residue so obtained to flash chromatography
(silica, 1:20 v/v triethylamine/methanol elution) provided, after
concentration of the appropriate fractions (RF 0.5 in 1:20 v/v
triethylamine/methanol), the title compound (+)-1 (22 mg, 85%)
as a white, crystalline solid, mp 121–124◦C (lit.[9b] mp 124–
125◦C), [α]D +108.8 (c 0.4, CHCl3) [Found: M+•, 287.1518.
C17H21NO3 requires M+•, 287.1521]. δH (800 MHz) 6.64 (d, J
8.2, 1H), 6.62 (d, J 8.2, 1H), 6.06 (d, J 10.3, 1H), 6.00 (ddd, J
10.3, 5.0, and 1.3, 1H), 4.61 (d, J 1.7, 1H), 4.14 (ddd, J 10.1, 5.1,
and 1.3, 1H), 4.09 (d, J 5.1, 1H), 3.83 (s, 3H), 3.68 (dd, J 5.1 and
0.8, 1H), 3.27 (t, J 13.2, 1H), 3.05 (d, J 13.2, 1H), 2.68 (dddd,
J 15.8, 6.5, 5.0, and 1.3, 1H), 2.40 (s, 3H), 2.28 (br s, 1H), 2.08
(dt, J 13.2 and 2.9, 1H), 2.00 (m, 1H), 1.58 (dd, J 13.2 and 2.1,
1H). δC (75 MHz) 145.9 (C), 144.3 (C), 133.1 (C), 129.3 (C),
127.7 (CH), 126.9 (CH), 122.2 (CH), 111.2 (CH), 88.8 (CH),
62.2 (CH), 60.7 (CH2), 56.0 (CH3), 53.9 (C), 48.3 (CH2), 42.2
(CH3), 33.9 (CH2), 30.0 (CH2). νmax (KBr)/cm−1 3563, 2919,
2849, 1625, 1592, 1507, 1438, 1280, 1047, 908, 732. m/z (EI,
70 eV) 287 (M+•, 94%), 286 (100), 270 (23), 244 (36), 230
(28), 216 (44), 174 (42), 115 (20), 85 (16), 71 (24), 57 (34),
43 (28).
Data for the Hemihydrate of bis-Ether 13
C17H21NO6·0.5(H2O), M 344.36, T 200 K, monoclinic,
space group P21,
Z 8, a 13.9312(2), b 14.5592(1),
c
17.2168(2) Å, β
106.0707(6)◦, V 3355.57(7) Å3, Dx
1.363 g cm−3, 10191 unique data (2θmax 60.2◦), R 0.034 [for
7031 reflections with I > 2.0σ(I)]; Rw 0.076 (all data), S 0.77.
Data for Compound 19
C17H21NO4, M 303.36, T 200 K, orthorhombic, space group
P212121, Z 4, a 8.3701(2), b 10.4272(3), c 17.8797(5) Å,
V 1560.48(7) Å3, Dx 1.291 g cm−3, 2062 unique data (2θmax
55◦), R 0.032 [for 1471 reflections with I > 2.0σ(I)]; Rw 0.070
(all data), S 0.79.
Structure Determination
Images were measured on a Nonius Kappa CCD diffracto-
meter(MoKα, graphitemonochromator, λ = 0.71073 Å)anddata
extracted using the DENZO package.[32] Structure solution was
by direct methods (SIR92).[33] The structures of the abovemen-
tioned compounds were refined using the CRYSTALS program
package.[34] Atomic coordinates, bond lengths and angles, and
displacement parameters have been deposited at the Cambridge
Crystallographic Data Centre (CCDC nos. 735777, 735778, and
739080 for compound 12, the hemihydrate of bis-ether 13 and

Chemoenzymatic Synthesis of (+)-Galanthamine
1447
compound 19, respectively). These data can be obtained free-of-
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contactingThe Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
http://questor.qub.ac.uk/Contact/ (accessed May 10, 2010). For
reviews on methods for generating cis-1,2-dihydrocatechols by micro-
bial dihydroxylation of the corresponding aromatics, as well as the
synthetic applications of these metabolites, see: (a) T. Hudlicky,
D. Gonzalez, D. T. Gibson, Aldrichimica Acta 1999, 32, 35.
(b) M. G. Banwell, A. J. Edwards, G. J. Harfoot, K. A. Jolliffe, M. D.
McLeod, K. J. McRae, S. G. Stewart, M. Vögtle, Pure Appl. Chem.
2003, 75, 223. doi:10.1351/PAC200375020223
Acknowledgements
The authors thank the Institute ofAdvanced Studies,TheAustralian National
University, and the Australian Research Council for generous financial sup-
port as well as Dr Hank Fales (National Institutes of Health, Maryland, USA)
for an authentic sample of (−)-galanthamine.
(c) R. A. Johnson, Org. React. 2004, 63, 117.
(d) T. Hudlicky, J. W. Reed, Synlett 2009, 685. doi:10.1055/S-0028-
1087946
[15] A. E. Wick, D. Felix, K. Steen, A. Eschenmoser, Helv. Chim. Acta
1964, 47, 2425. doi:10.1002/HLCA.19640470835
[16] J. Mulzer, J. W. Bats, B. List, T. Opatz, D. Trauner, Synlett 1997, 441.
[17] For useful reviews of the Pictet–Spengler reaction see:
(a) E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797.
(b) M. Lorenz, M. L. Van Linn, J. M. Cook, Curr. Org. Synth. 2010,
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[18] For examples of related nucleophilic ring cleavage reactions of com-
pound 4 see: M. G. Banwell, N. Haddad, T. Hudlicky, T. C. Nugent,
M. F. Mackay, S. L. Richards, J. Chem. Soc., Perkin Trans. 1 1997,
1779. doi:10.1039/A700733G
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[14] Compound 2 can be obtained from the Aldrich Chemical Co.
(Catalogue Number 489492) or from Questor, Queen’s Univer-
sity of Belfast, Northern Ireland. Questor Centre Contact Page: